1. Field of the Invention
The present invention generally relates to multidrug resistance and chemosensitizing agents. Specifically, the present invention relates to chemosensitizing agents for treating multiple drug resistant strains of Plasmodium falciparum. 
2. Description of the Related Art
Multiple drug resistance (MDR) occurs when target cells, such as cancer cells, bacteria and protozoa, become resistant during treatment to the drug being used and to other drugs that are different and structurally unrelated to the drug. See Nooter, et al. (1991) Br. J. Cancer 63:663-669. Compounds such as verapamil, diltiazem, cyclosporin and catharanthine are known to attenuate or reverse drug resistance in some cells. However, not all cells that develop MDR are responsive to known chemosensitizing agents and some chemosensitizing agents are only active in vivo at or near toxic levels. Additionally, antipsychotic, antihistaminic or cardiovascular side effects are associated with some chemosensitizing agents.
MDR is a prevalent problem in the treatment of many diseases and infections. For example, the increasing prevalence of MDR strains of Plasmodium falciparum in most malaria endemic areas has significantly reduced the efficacy of current antimalarial drugs for treating, preventing or inhibiting malaria. Resistance to the inexpensive antimalarial mainstays, such as chloroquine, is problematic worldwide. Unfortunately, resistance to mefloquine, which was proposed as the drug of choice for chloroquine-resistant malaria, has been reported from Africa and Southeast Asia. See Nosten, F., et al. (1982) Lancet 337:1140-1143; and Oduola, A. M., et al. (1987) Lancet 2:1304-1305.
A wide variety of drugs representing different drug classes and diverse chemical structures have been shown to reverse chloroquine resistance in P. falciparum in vitro. See Gerena, L., et al. (1992) Antimicrobial Agents and Chemotherapy 36:2761-2765; Bitonti, A. J., et al. (1988) Science 242:1301-1303; and Ye, Z. G., et al. (1989) Biochem Biophys. Res. Comm. 159:242-248. These include calcium channel blockers (verapamil) and calmodulin antagonists (trifluoperazine and phenothiazines), which could be co-administered with chloroquine to effectively potentiate its efficacy against chloroquine resistant cell lines. See Kyle, D. E., et al. (1990) In Vitro. Trans. Royal Soc. Trop. Med. Hyg. 84:474-478 and Ford, J. M., et al. (1989) Mol. Pharmacol. 35:105-115. However, the clinical value of these compounds as MDR reversing agents is impaired by their profound antipsychotic, antihistaminic or cardiovascular side effects. Additionally, the effective dose of these compounds as chemosensitizing agents is generally close to or higher than the therapeutic dose for other clinical applications.
Extensive structure-activity relationship studies of neoplastic MDR modulators with diverse chemical structures have established two pharmacophores for resistance reversal activity: a hydrophobic tricyclic aromatic ring and a specific side chain with two amino groups separated by two or three carbons from the aromatic ring. Tertiary substituted amines are more potent than secondary or primary amines. However, antipsychotic and antihistaminic agents also share similar structural features, except for the length of side chain, as those of chemosensitizing agents. See Magid, R. M., et al. (1981) J. Org. Chem. 46:824-825.
For example, phenothiazines with ring nitrogen and side chain nitrogen separated by two carbons showed the best antihistaminic activity and those separated by three carbons exhibited the strongest antipsychotic activity. Thus, the length of side chain affects the pharmacological properties of the molecule. While the optimal side chain length of phenothiazine and related compounds for antihistaminic and antipsychotic activities is limited to 2-3 carbons, the optimal side chain length for anti-MDR activity has yet to be discovered.
Therefore, a need exists for chemosensitizing agents with improved anti-MDR efficacy and reduced side effects to restore the clinical efficacy of current drugs such as antimalarial drugs.
The present invention relates to a compound having the structural formula 
or a pharmaceutically acceptable salt or prodrug thereof, wherein X is a substituted or unsubstituted alkyl or a heteroatom; n is 4, 5 or 6; Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or 
wherein R1 and R2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
In some embodiments, X is C, S, or ethyl.
In some embodiments, Y is pyrrolidinyl, piperidinyl, morpholinyl, or 4-methylpiperazinyl.
In some embodiments, R1 and R2 are each independently, methyl, ethyl, or benzyl.
The compound of the present invention modulates, attenuates, reverses, or affects a cell""s or organism""s resistance to a given drug or compound such as an antimalarial.
Preferred compounds of the present invention include
10-(4-Dimethylaminobutyl)phenothiazine,
10-(4-Diethylaminobutyl)phenothiazine,
10-(4-Methylbenzylaminobutyl)phenothiazine,
10-(4-Dibenzylaminobutyl)phenothiazine,
10-(4-Pyrrolidin-1-yl-butyl)phenothiazine,
10-(4-Piperidin-1-yl-butyl)phenothiazine,
10-(4-Morpholin-4-yl-butyl)phenothiazine,
10-[4-(4-Methyl-piperazin-1-yl)-butyl]phenothiazine,
5-(4-Dimethylaminobutyl)iminodibenzyl,
5-(4-Diethylaminobutyl)iminodibenzyl,
5-(4-Methylbenzylaminobutyl)iminodibenzyl,
5-(4-Dibenzylaminobutyl)iminodibenzyl,
5-(4-Pyrrolidin-1-yl-butyl)iminodibenzyl,
5-(4-Piperidin-1-yl-butyl) iminodibenzyl,
5-(4-Morpholin-4-yl-butyl)iminodibenzyl,
5-[4-(4-Methyl-piperazin-1-yl)-butyl]iminodibenzyl, 5-(4-Diethylaminobutyl)iminostilbene,
5-(4-Pyrrolidin-1-yl-butyl)iminostilbene,
N,N-Diethyl-Nxe2x80x2,Nxe2x80x2-diphenyl-butane-1,4-diamine,
Diphenyl-(4-pyrrolidin-1-yl-butyl)amine,
5-(5-Diethylaminopentyl)iminodibenzyl,
5-(5-Pyrrolidin-1-yl-pentyl)iminodibenzyl,
5-(6-Diethylaminohexyl)iminodibenzyl, and
5-(6-Pyrrolidin-1-yl-hexyl)iminodibenzyl.
In some embodiments, the present invention relates to a pharmaceutical composition comprising a compound having the structural formula 
or a pharmaceutically acceptable salt or prodrug thereof, wherein X is a substituted or unsubstituted alkyl or a heteroatom; n is 4, 5 or 6; Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or 
wherein R1 and R2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each aromatic ring structure may be independently substituted or unsubstituted; and a pharmaceutically acceptable excipient. The pharmaceutical composition may further comprise a supplementary active compound.
The present invention also relates to a chemosensitizing agent comprising a compound having the structural formula 
or a pharmaceutically acceptable salt or prodrug thereof, wherein X is a substituted or unsubstituted alkyl or a heteroatom; n is 4, 5 or 6; Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or 
wherein R1 and R2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
In some embodiments, the fractional inhibitory concentration of the chemosensitizing agent is less than 0.6, preferably less than about 0.5, preferably less than about 0.4, preferably less than about 0.3, more preferably about less than about 0.2. The compound of the chemosensitizing agent modulates, attenuates, reverses, or affects a cell""s or organism""s resistance to a given drug or compound such as an antimalarial.
In some embodiments, the present invention relates to a method of modulating, attenuating, reversing, affecting, or a combination thereof, a cell""s or organism""s resistance to a given drug comprising administering a compound having the structural formula 
or a pharmaceutically acceptable salt or prodrug thereof, wherein X is a substituted or unsubstituted alkyl or a heteroatom; n is 4, 5 or 6; Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or 
wherein R1 and R2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
In some embodiments, the present invention relates to a method of treating, preventing, or inhibiting malaria in a subject comprising administering to the subject a therapeutically effective amount of a compound having the structural formula 
or a pharmaceutically acceptable salt or prodrug thereof, wherein X is a substituted or unsubstituted alkyl or a heteroatom; n is 4, 5 or 6; Y is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or 
wherein R1 and R2 are each independently, H, a heteroatom, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and wherein each aromatic ring structure may be independently substituted or unsubstituted.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute part of this specification, illustrate several embodiments of the invention and together with the description serve to explain the principles of the invention.